A single enzyme targets a parasite’s weak spot

In freshwater lakes throughout Africa, the Middle East, and Southeast Asia, snails slither across the rocky shores harboring a deadly secret. These snails release worms into the waters that are responsible for one of the most devastating parasitic infections, schistosomiasis, ultimately putting more than 700 million people at risk for infection (1). Primarily affecting poor and rural communities, specifically agricultural and fishing populations, schistosomiasis kills about 200,000 people a year (2).

Currently, there is only one drug available on the market to treat schistosomiasis, Praziquantel (PZQ), which has limited activity against juvenile worms. In the search of alternatives to PZQ, a team of researchers discovered several compounds targeting an enzyme critical for the parasite’s survival. The inhibitors showed successful schistosomicidal activity in mice infected with the parasite, the authors reported in Nature Communications (3).

David Williams , a biochemist at Rush University and author of the study has been researching schistosomiasis for more than 25 years. “I was living in West Africa and was potentially exposed to schistosomiasis almost every day,” he said, reflecting on the motivation behind his work. “I feared it because there was no effective roadmap [to treatment] at the time.” Williams’s goal is to begin to lay down that map.

This is like magic because you don’t really inject that much. There’s just a tiny speck of this compound and it works.
– Pavel Petukhov , University of Illinois Chicago

He and his team began by looking for proteins or mechanisms in worms that are unique or significantly different from those in humans. The thioredoxin glutathione reductase (TGR), a component of the antioxidant pathway, is one of these enzymes in schistosomiasis parasites. While humans possess two separate flavoprotein oxidoreductases to maintain redox homeostasis, schistosome worms use only the TGR to carry out the activities of both enzymes (4).

The researchers first selected several small molecular TGR inhibitors that are currently available but cause adverse side effects (5). Using X-ray crystallography, they pinpointed the binding site for these molecules on the protein. Then the team designed compounds that bound to that same site to ultimately test them in worms and mice. Several compounds outperformed PZQ’s efficacy against adult and juvenile worms. When the team evaluated the most promising of them in a mouse model of schistosomiasis infection, they found that three of these compounds significantly decreased both worm and egg burdens.

“This is like magic because you don’t really inject that much,” said Pavel Petukhov, a chemist at the University of Illinois and coauthor of the study. “There’s just a tiny speck of this compound, and it works.”

To translate this clinically, there is still a long way to go. “Now that we’ve seen [that these inhibitors are] effective in mice, will they be effective in rats?” asked Stefan Debbert, an organic chemist at Lawrence University who was not involved in the study. “This paper seems to find some compounds that are effective against both life stages, which is pretty huge,” he added.

While this research takes an important step towards developing new drugs for treating schistosomiasis, the researchers are also exploring other therapeutic avenues. “All parasitic flatworms that are like schistosomes . . . have the same redox system and depend on the same enzyme, TGR, exclusively,” explained Williams. “So, we should, in theory, be able to target that protein from lots of different parasitic worms with this approach.”